Fluoroalkylation: Expansion of Togni Reagents
Introduction
The introduction of highly fluorinated groups in drug and pesticide candidate compounds is a powerful strategy to modulate their properties. The introduction of fluorinated side chains can modulate acid-base and lipophilicity, impart a dipole moment, lock confirmation, and mitigate undesirable metabolic degradation of the parent compound. Due to the limitations of the synthetic route, fluorine-containing groups are usually limited to a single fluorine or trifluoromethyl group. By developing a new set of reagents, more refined fluoroalkylations are now possible. Current fluoroalkylation tools include Togni reagents, high valent iodine perfluorinated alkylation reagents, fluoroalkyl bromides, silanes, carboxylates, and sulfonyl fluorides that are versatile for late stage fluoroalkylations, while being compatible with a wide range of sensitive functional groups and having broad applicability.
HYPERVALENT IODINE REAGENTS
In the last decade, Togni reagents have become a standard tool to provide a viable route for compound trifluoromethylation for drug and pesticide development. 1 These highly valent iodine compounds are electrophilic CF3 transfer reagents for direct, mild and efficient trifluoromethylation and in many cases act as key reaction intermediates via trifluoromethyl radicals.
Recently, other cyclic high-valent iodine reagents with improved hydrolytic stability and thermal stability have been developed as mild and easily handled electrophilic chlorination, fluorination, and azidation reagents. Easily storable fluoroiodane reagents allow good fluorine functionalization and fluorocyclization of olefins under mild conditions, while azidoiodane reagents can be used as electrophilic azide reagents for the azidation of enolates.
TOGNI PERFLUOROALKYL REAGENTS
Many types of transformations can also be performed using CF3-Togni reagents, resulting in a rare and potentially attractive fluorinated chemical space.2
With an "extended set of Togni reagents", the lead compounds can be diversified in the final stages of synthesis to provide hard-to-obtain fluoroalkyl modified derivatives.
2CF2-"extended Togni reagent" undergoes radical cyclization with olefins and acetylenes to obtain rare tetrafluoroheterocyclic functional groups. 3 The partial incorporation of -CF2CF2- into the cyclic structure gives the molecule a unique combination of properties called "polar hydrophobicity" - a permanent electric dipole combined with the hydrophobicity of the tetrafluoroethylene unit.
FLUOROALKYL BROMIDES
The substituted fluoroalkyl bromides become powerful nucleophilic fluoroalkylation reagents after metallization by isopropylmagnesium chloride-lithium chloride complexes (Turbo-Grignard). 4 The in situ generated fluoroalkylmagnesium chloride intermediates are moderately stable up to -40 °C and can be efficiently trapped with various electrophiles to give -CF2CF2-linked products.
FLUOROALKYL SILANES
Fluorosubstituted alkyl silanes are used as traditional nucleophilic sources of fluoroalkylated synthons. When activated with catalytic fluorides or alcohol salts, they can fluoroalkylate a range of aldehydes, reactive ketones, or imines. Silanes can also be involved in the transition metal-catalyzed formation of R-CF2CF2-substituted aromatic compounds.
TETRAFLUOROPROPIONATES
β-substituted cesium tetrafluoropropionate is a convenient raw material for the construction of fluorinated alkylcarbamides. The pKa of such amide groups are significantly lower than those of their non-fluorinated counterparts, greatly enhancing the physiological and pharmacological potential of this compound as a drug candidate molecule. Compared with free carboxylic acids, which are highly hygroscopic, the hygroscopicity of cesium salts is reduced, so that the reactions associated with cesium salts can be operated under air conditions.
FLUOROALKYLSULFONYL FLUORIDES
Fluoroalkyl sulfonyl fluorides can be used as electrophilic fluoroalkyl sulfonylation reagents with moderate reactivity. Although the fluoroalkyl sulfonyl chloride with its same properties can also act as an electrophilic chlorination reagent for amines to provide unwanted N-chlorinated amines, the slow reaction rate and clean reaction system of the nitrogen sulfonylation reaction when the fluoroalkyl sulfonyl fluoride is involved as a reactant gives the corresponding sulfonamide. The fluorinated alkyl sulfonylation of the amino nitrogen atom greatly reduces the pKa of the NH group for modulating the behavior of the candidate drug molecule or for building additional molecular complexity around the highly acidic fluorinated alkyl sulfonamide.
Conclusion
Due to its increasing relevance for the biopharmaceutical field and the crop protection industry, organofluorine chemistry is increasingly dependent on the development of novel reagents and reactions. The concept of this new class of functionalized tetrafluoroethyl reagents based on hypervalent iodine scaffolds that can transfer effective fluorine atoms to a large number of organic molecules has facilitated the development of their extension to more complex fluoroalkyl groups.
Reference
1.Charpentier J, Früh N, Togni A. 2015. Electrophilic Trifluoromethylation by Use of Hypervalent Iodine Reagents. Chem. Rev.. 115(2):650-682. https://doi.org/10.1021/cr500223h
2.Matoušek V, Václavík J, Hájek P, Charpentier J, Blastik ZE, Pietrasiak E, Budinská A, Togni A, Beier P. 2016. Expanding the Scope of Hypervalent Iodine Reagents for Perfluoroalkylation: From Trifluoromethyl to Functionalized Perfluoroethyl. Chem. Eur. J.. 22(1):417-424. https://doi.org/10.1002/chem.201503531
3.Charpentier J, Früh N, Foser S, Togni A. 2016. Tandem Radical Fluoroalkylation?Cyclization: Synthesis of Tetrafluoro Imidazopyridines. Org. Lett.. 18(4):756-759. https://doi.org/10.1021/acs.orglett.6b00018
4.Budinská A, Václavík J, Matou?ek V, Beier P. 2016. Nucleophilic Tetrafluoroethylation Employing in Situ Formed Organomagnesium Reagents. Org. Lett.. 18(22):5844-5847. https://doi.org/10.1021/acs.orglett.6b02890